TY - JOUR
T1 - Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality
AU - Saha, Asim
AU - Aoyama, Kazutoshi
AU - Taylor, Patricia A.
AU - Koehn, Brent H.
AU - Veenstra, Rachelle G.
AU - Panoskaltsis-Mortari, Angela
AU - Munn, David H
AU - Murphy, William J.
AU - Azuma, Miyuki
AU - Yagita, Hideo
AU - Fife, Brian T.
AU - Sayegh, Mohammed H.
AU - Najafian, Nader
AU - Socie, Gerard
AU - Ahmed, Rafi
AU - Freeman, Gordon J.
AU - Sharpe, Arlene H.
AU - Blazar, Bruce R.
N1 - Funding Information:
This work was supported in part by grants from the National Institutes of Health Research Program (P01), National Institute of Allergy and Infectious Diseases (AI056299) (to M.H.S., N.N., R.A., G.J.F., A.H.S., and B.R.B.); Research Project Grant Program (R01), Institute of Allergy and Infectious Diseases (AI034495), Heart, Lung
PY - 2013
Y1 - 2013
N2 - Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic andendothelial cells expressed PD-L1.PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.
AB - Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic andendothelial cells expressed PD-L1.PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.
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U2 - 10.1182/blood-2013-05-500801
DO - 10.1182/blood-2013-05-500801
M3 - Article
C2 - 24030385
AN - SCOPUS:84891708632
VL - 122
SP - 3062
EP - 3073
JO - Blood
JF - Blood
SN - 0006-4971
IS - 17
ER -